Multiple human papillomavirus infections are highly prevalent in the ...

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Dec 16, 2014 - We found a very high prevalence of HPV infections among this cohort (86%), with more than one fourth of them (28%) positive for type 16.
Méndez-Martínez et al. BMC Infectious Diseases 2014, 14:671 http://www.biomedcentral.com/1471-2334/14/671

RESEARCH ARTICLE

Open Access

Multiple human papillomavirus infections are highly prevalent in the anal canal of human immunodeficiency virus-positive men who have sex with men Rocío Méndez-Martínez1, Norma E Rivera-Martínez2, Brenda Crabtree-Ramírez2, Juan G Sierra-Madero2, Yanink Caro-Vega2, Silvia C Galván4, David Cantú de León3 and Alejandro García-Carrancá5,6*

Abstract Background: Anal cancer has become one of the most common non-AIDS-defined tumors among Human Immunodeficiency Virus-positive (HIV+) individuals, and a rise in its incidence among HIV+ Men who have Sex with Men (MSM) has been shown, despite the introduction of Highly Active Anti-Retroviral Therapy (HAART). Human Papillomavirus (HPV) infections are highly prevalent among HIV+ MSM and recent studies have shown high rates of HPV-associated anal intraepithelial neoplasia (AIN) and anal cancer among this population. Methods: In the present study we determined the prevalence and nature of HPV co-infections in the anal canal of 324 HIV+ MSM attending a high specialty medical center in Mexico City, DNA extraction and amplification with generic primers for HPV was performed, followed by detection of specific types and co-infections with INNO-Lipa, and identification of variants by amplification and sequencing of the E6 and LCR region of HPV 16. Results: We found a very high prevalence of HPV infections among this cohort (86%), with more than one fourth of them (28%) positive for type 16. Among HPV16-positive patients, European variants were the most prevalent, followed by Asian-American ones. Among these individuals (HPV-16+), we identified co-infections with other 21 HPV types namely; 11, 51, 52, 6, 66, 68, 74, 18, 45, 35, 26, 44, 70, 53, 54, 82, 31, 33, 56, 58, 59. Conclusions: HIV+ MSM show a very high rate of HPV infections in the anal canal and those with type 16 exhibited a multiplicity of associated types. This study emphasizes the need for an early detection of HPV infections among HIV+ MSM in order to establish its utility to prevent anal neoplasia and cancer. Keywords: HIV, HPV, MSM, Type 16, Variants, Anal cancer

Background HPV are well known for their association with cervical cancer [1], and have also been shown to play a role in the pathogenesis of distinct squamous cell cancers, including anal [2,3], penile [4,5], oropharyngeal [6,7] vulvar, and conjunctival [8] cancers. Concurrent infection with HIV may facilitate or accelerate the pathological consequences of * Correspondence: [email protected] 5 Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cancerología, SSA, México D.F., Mexico 6 Laboratory of Virus & Cancer Instituto Nacional de Cancerología, Av. San Fernando No. 22, Colonia Sección XVI, México D.F., Tlalpan 14080, México Full list of author information is available at the end of the article

HPV infections. Persistent HPV infections are very frequent among HIV+ MSM [9]. Anal HPV infections, which contribute to the development of anal warts and anal cancer, are very common among MSM, especially HIV+ individuals [10] and HPV-associated ano-genital malignancies occur particularly in patients with Acquired Immunodeficiency Syndrome (AIDS) [11]. HIV+ MSM are at 37-fold greater risk of invasive anal cancer. Likewise, the incidence of anal cancer and anal intraepithelial neoplasia (AIN), the potential precursor lesion of squamous cell carcinoma of the anus is very high among HIV+ MSM [12] and a definite increasing trend in the incidence of anal cancer has

© 2014 Méndez Martínez et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Méndez-Martínez et al. BMC Infectious Diseases 2014, 14:671 http://www.biomedcentral.com/1471-2334/14/671

been shown despite the use of Highly Active Antiretroviral Therapy (HAART) [13]. Infections with HPV represent the most common sexually transmitted disease worldwide. HPV is a double-stranded DNA virus, and 160 different types of HPV officially described have been found at mucosal or cutaneous sites, each with a specific tissue tropism. At least 30 of them have been identified with high predilection for the ano-genital tract. Specific types, such as 6 and 11, are classified as low-risk (LR) types because they have been found to be associated only with benign lesions. In contrast, high-risk (HR) types, including most notably 16 and 18, have been found to be associated with both low- and high-grade anal squamous intraepithelial lesions (ASIL) as well as the majority of cervical and anal cancers [14,15]. Risk factors for the presence of anal HPV include the presence of anal warts and a history of receptive anal intercourse, HIV infection, and a low CD4 cell count [16]. In a Spanish cohort HR and LR HPV types were very prevalent in the anus of HIV+ MSM (83% and 72.7%, respectively), with type 16 being the most common one. Concurrent infection with several HPV types was also common among HIV+ MSM (58.5%) [17]. In addition, HIV+ men have higher rates of HPV anal infection and higher levels of HPV type 16 than HIV- men [16,18]. In a recent study in immunocompetent heterosexual men, the incidence of overall ano-genital HPV infections was 24.8% [19]. The anal and cervical epithelia possess similar embryonic origins. Histologically, columnar epithelium with a transition zone (with increased metaplastic activity) and a more differentiated squamous epithelium are observed. The anal and cervical epithelia are infected by the same types of HPV, producing similar manifestations that

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range from condyloma to squamous intraepithelial lesions (SILs) and cancer. The fact that multiple concurrent infections with HPV constitute an associated morbidity among patients infected with HIV has only recently been recognized [20]. In Mexico, there have been few reports describing the prevalence of anal HPV among HIV+ MSM. In 2002, we studied a group of 31 HIV+ MSM from Mexico City and detected HPV in the anal canal of 74.2% of the cases; 67.7% were positive for HR HPV types (hcII test B: 16/18/ 31/33/35/39/45/51/52/56/58/59/68), and 64.5% were positive for LR HPV types (hcII test A: 6/11/42/43/44) [21]. In this study, we determined the prevalence of HPV types infecting the anal canal of HIV+ MSM and characterized the type 16 variants. In addition, we characterized the HPV types associated with HPV type 16 in the anal canals of these patients.

Methods Samples

We analyzed 324 anal exudates from HIV+ MSM patients attending the HIV Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” (INCMNSZ) in Mexico City. Patients over 18 years old, who presented to care between August and December 2008, were invited to participate. Samples were obtained with a cytobrush and inserted into a tube collector containing PreservCyt. The study was approved by the Ethics Committees of INCMNSZ SSA, and the Instituto Nacional de Cancerología, SSA. Written informed consent was obtained from all of the participants. Data collection

Socio-demographic, clinical and sexual behavior information was collected using a self-applied written questionnaire, with

Table 1 Demographic and Clinic characteristics of patients included Variable

Total N = 324

HPV+ N = 279

HPV- N = 45

p-value

Age

39 (33–45)

38 (32–44)

42 (35–49)

0.015

Education year

12 (10–16)

12 (10–18)

12 (10–16)

0.777

Employed

206 (64)

179 (65)

27 (59)

0.637

CD (cells/mL)

414 (267–592)

409 (267–578)

459 (287–699)

0.267

Viral Suppression

268 (83)

228 (82)

41 (91)

0.127

Time since diagnoses (years)

6.22 (2.99-9.9)

6.12 (2.80-9.47)

7.80 (4.29-12.0)

0.077

Time since treatment (years)

2.76 (0.5-6.2)

2.60 (0.50-6.00)

3.77 (0.96-7.39)

0.212

PI

99 (31)

88 (32)

11 (24)

0.718

NNRTI

175 (54)

148 (55)

27 (61)

Other

39 (12)

33 (12)

6 (13)

Regiment of *HAART Initiation

Notes: Median and Interquartile range reported for continuous variable. Number of patients and percentage reported for categorical variables. Viral suppression defined as HIV-RNA